5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamides and method of preparation thereof

ABSTRACT

The compounds 5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamide, 5amino-1-(m-chlorophenyl)-3-ethyl-4-pyrazolecarboxamide, and 5amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide, are described. They are useful as analgetic and antiinflammatory agents in warm-blooded animals.

United States Patent 1 Marsico, Jr. et al.

[451 Feb. 4, 1975 5-AMlNO -3-ETHYL-l-PHENYL-4- PYRAZOLECARBOXAMIDES ANDMETHOD OF PREPARATION THEREOF [75] Inventors: Joseph William Marsico,Jr., Pearl River, N.Y.; Joseph Peter Joseph, Cliffside Park, N.J.; LeonGoldman, Nanuet, N.Y.

[73] Assignee: American Cyanamid Company,

Stamford, Conn.

[22] Filed: May 3, 1973 [21] Appl. No.: 356,979

Related [1.8. Application Data [63] Continuation-in-part of Ser. No.248,990, May 1,

1972, Pat. NO. 3,760,082.

[52] US. Cl. 260/310 R, 424/273 [51] Int. Cl C07d 49/20 [58] Field ofSearch 260/310 R [56] Reterences Cited UNITED STATES PATENTS 2,925,4182/1960 Druey et a1. 260/310 R 2,965,643 12/1960 Druey et a1 260/310 R3,187,006 6/1965 Druey et al. 260/310 R 3,487,083 12/1969 Cresswellet a13 l0-'R Primar y Examiner-Natalie Trousof Attorney, Agent, orFirm-Ernest Y. Miller 5 Claims, N0 Drawings I -AMINO-3-ETHYL-l-PHENYL-4-PYRAZOLECARBOXAMIDES AND METHOD OF PREPARATION THEREOF DESCRIPTION OFTHE INVENTION The active components of this invention are S-amino-3-ethyl-l-phenyl-4-pyrazolecarhoxumides of the formula:

coma N l NHQ NHNH2 C Hs NC c ns CN H R NC oc as NR2 I II CONH;

' wherein R is hydrogen. chloro or fluoro.

The hydrazine (l) is condensed with l.-ethoxypropylidene)malonitrile(ll) in an organic solvent such as ethanol to yield the5-amino-3-ethyl-l-phenyl or (substituted phenyl)-4-pyrazolecarbonitrile(III) which is hydrolyzed to produce the desired 5-amino-3-ethyll-phenylor (substituted phenyll-4- pyrazolecarboxamide (IV). The hydrazine (I)may be used as the free base in the reaction or may be generated in situby utilizing a mixture of the hydrazine (l) hydrochloride and sodiumacetate. The hydrolysis of the carbonitrile (Ill) to the carboxamide(IV) may be accomplished with sodium hydroxide or with concentratedsulfuric acid. Acid addition salts of the pyrazoleearboxamides can beprepared by the treatment with acid such as mineral acids, for examplehydrochloric acid to produce 5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamide hydrochloride, which is well known to those skilledin the art.

The 5-amino-3-ethyl-l-phenyl or (substituted phenyl)-4-pyrazolecarboxamides of the present invention are highly activeanalgeti e agents in warm-blooded animals. They are useful in dosesranging from about 1 to mg. per kilogram per day of warm-blooded animal.The preferred range of dose is usually 5 to 20 mg. per kilogram per day.

For therapeutic administration, the 5-amino-3-ethyll-phenyl or(substituted phenyl)-4- pyrazolecarboxamides of this invention may beincorporated with excipients and used, for example, in the form oftablets, dragees, capsules, suppositories, liquids, clixirs, emulsions,suspensions, syrups, chocolate, candy, wafers, chewing gum, solutionsfor parenteral administration, or the like. Such compositions andpreparations should contain at least 0.1% of the active compound. Thepercentage in the composition and preparations may, of course, bevaried, and may conveniently be between about 2% and 60% or more of theweight of the unit. The amount ofa 5-amino-3-ethyl-lphenyl or(substituted phenyll-4-pyrazolecarboxamide in such therapeuticallyuseful compositions or preparations is such that a suitable dosage willbe obtained. This dosage can also be obtained by the use of sustainedrelease preparations. Preferred compositions or preparations accordingto the present invention are prepared so that a dosage unit formcontains between about I and about 250 milligrams of a5-amino-3-ethyll-phenyl or (substituted phenyl)-4 pyrazolecarboxamide.

Tablets, pills, dragees, and the like may contain the following: abinder such as gum tragaeanth, acacia, corn starch, or gelatin; adistintegrating agent such as corn starch, potato starch. alginic acid,or the like; a lubricant such as stearic acid, magnesium stearate, talcor the like; a sweetening agent such as sucaryl or saccharin may beadded, as well as a flavoring such as peppermint, oil of Wintergreen orcherry flavoring.

The active components of the present invention are active as analgeticagents when measured by the writhing syndrome" test for analgeticactivity as described by Siegmund et al., Proceedings of the Society forExperimental Biology and Medicine, Vol. 95, p. 729 (1957), withmodifications. This method is based upon the reduction of the number ofwrithes following the intraperitoneal injection of one mg./kg. of bodyweight of phenyl-p-quinone in male Swiss albino mice weighing 15-25grams per mouse. The syndrome is characi I 3,864,359 3 4 terized byintermittent contractions of the abdomen. tion thresholds is calculated.The following Table ll twisting and turning of thetrunk, and extensionof the summarizes the results obtained bytesttng representahind legsbeginning 3 to minutes after injection of the tive compounds. I

TABLE ll Efi'ect of Analgetic Compounds on the Pain Threshold of Ratswith inflamed Paws PostTreatment/Pre-Treatment Pressure Threshold(Average of 8 Rats Each Time Period) Oral Dose Hours After TreatmentCompound mg./kg. of Body Weight 1 2 5-Amino-3-ethyl-lphenyl-4-pyrazole-200 3.7 1.8 l.7

carboxamide 5-Amino-3-ethyl-lpyrazolecarboxamide Aspirin 200 1.1 1.1 L6

phenyl-p-quinone. The test compound is administered In determining theacute anti-inflammatory activity orally to groups of two mice each 30minutes before inof the present compounds Royal Hart, Wistar strain.jection of the phenyl-p-quinone. The total number of rats ranging from80 to .90 g. were used. The rats were writhes exhibited by each group ofmice is recorded for fasted overnight prior to dosing but had freeaccess to a 3-minute period commencing 15 minutes after injecwater. Thedrugs in aqueous suspension were administion of the phenyl-p-quinone. Acompound is considtered by gavage in a volume of 1.7 ml./50 g. rat(correered active if it reduces the total number of writhes in sponds tohydration volume used by Winter, et al., two test mice from a controlvalue of approximately 30 per pair to a value of l8 or less. Thefollowing Table l Proc. Soc. Exp. Biol. Med, ll 1, 544-547, 1962). The

summarizes the relative activity of the present comphlogistic agent usedwas carrageenin prepared as a pounds as active analgetics, and comparesthem with sterile 1% suspension in 0.9% sodium chloride for routhereference drug aspirin. tine testing. A volume of 0.05 ml. was injectedthrough TABLE I Analgetic Activity in the Antiwrithing Test Dose (Oralmg./kg. of Number of Writhes Compound Body Weight Pair No. l Pair No. 2

5-Amino-3-ethyll-phenyl-4-pyrazole- 100 0 3 carboxamide5-Amino-3-ethyll-(m-fluorophenyl)- I00 1 4 8 4pyrazolecarboxamide5-Amino-3-ethyl-l- (m-chlorophenyl)-4- 100 9 5 pyrazolecarboxamideAspirin 100 l (historical average) Experiments are conducted todetermine analgesia a 26 gauge needle into the plantar tissue of theright by a modification of the method of Randall and Selitto hind paw.Measurements were made 5 hours after drug (Arch. Int. Pharmacodyn,lllz409-4l9, I957). This administration (4 hours after carrageeninchallenge) method is used to measure the pain threshold of rats unlessotherwise indicated. Volumes of both the norwhose paws were madesensitive to pressure by injecmal and carrageenin inflamed feet weredetermined. tion ofa 20% aqueous suspension (0.] ml.) of brewers Thedifference between the two measurements was yeast into the plantarsurface of the left hind paw. The considered to be the increased edemadue to the carrapressure in grams which, when applied to the ingeeninadministration. Results were expressed as a C/T flammed paw, elicits asudden struggle or vocalization efficacy ratio (edema of Cont oanimals/edema of is recorded. A maximum (cutoff) pressure of 250 treatedanimals). The following Table lll summarizes grams is employed. Controlrats-respond at a pressure the results obtained with representativecompounds of of about 25 grams. A ratio of post/pretreatment reacthepresent invention.

TABLE 111 The effects of anti-inflammatory agents on carrageenin inducededema of the rat paw (pooled data) Ratio control/ Rats fasted overnightprior to testing. 2 Measurements made hours after oral administration.

Tests to show activity against chronic inflammation in adjuvantarthritis were carried out. Groups of three Royal Hart Wistar strainrats, weighing 200 i g. each, were injected intradermally in the righthind paw with Freunds adjuvant (dried human tubercle bacilli in amineral oil vehicle) at a dose of 2 mg./kg. of body weight. Testcompounds were administered orally in a 1.5% starch vehicle at theindicated dosage in mg./kg.

results are expressed as percent inhibition of swelling as compared tocontrols at the same time, the other inflamed sites, such as cars, pawsand tail (secondary lesions) are observed and the rat graded as todegree of inflammation and swelling present. The grading is based on ascale ofO to 24.0, where 0 represents a complete absence ofinducedarthritis nodules and 24.0 represents the maximum degree ofinflammation. The

of body weight once daily on days 0 through 13 postmean grade for eachtreated group is calculated and the challenge. Control rats Were treatedin 21 imilar fineffects of each representative compound tested are exbutgiven Starch Vehicle instead of the test pressed as percent inhibitionof the control grade. The pound. On the 14th and 21st day post-challengethe dif ll i T bl IV summarizes th lt Table IV The effect ofanti-inflammatory agents on adjuvant arthritis of rats (treatment day 0to day 13) Oral dose Dead/treated Mean weight 71 Inhibi i Treatmentmg./kg./day at 21 days gain (gms.) of swelling (primary lesion) Day 14Day 21 Day 14 Day 21 Normal Rats 4/51 69 1 10" Adjuvant controls 21/23436 39 0 0 Phenylbutazone I50 0/ 1 8 44" 75 2/18 57" 54 72" 23" 37.5 2/1847 50 67" I9 Aspirin 400 4/ l 8 48 57 76 68" 200 1/18 31 27 51" 36" 7/1842 49 40" 21" 5-Amino-3-ethy11-phenyl-4-pyrazolecarboxamide 50 2/14 2525 42" 13 S-Amino- 1 m-chlorophenyl )-3-ethyl-4-pyra2olecarboxamide 505/21 0 14 42 24 5-Amino-3-ethyl-l-(m-fluorophenyl)-4-pyrazo1e- 50 4/18 526 55 41 carboxamide 25 1/9 13 a 21 49 0 12.5 0/9 30 31 19 0Significantly different from adjuvant controls (p= 0.05 by t test)ameter of the injected paw (primary lesion) is measured by micrometercaliper, the volumes of inflamed paws are estimated from thesemeasurements, and the DETAlLED DESCRIPTION This invention is describedin greater detail in conjunction with the following specific examplesshowing preparation of the present compounds and compositions containingthe same.

EXAMPLE 1 Preparation of -Amino-3-ethyl-l-phenyl-4- pyrazoleearbonitrileA mixture of 22.5 g. of (l-ethoxypropylidene)- malononitrile, 21.7 g. ofphenylhydrazine hydrochloride and 12.3 g. of sodium acetate in 300 ml.of absolute ethanol is heated under reflux for 24 hours. The solvent isremoved under reduced pressure to give an oil which crystallizes ontrituration with hexane. The crystals are removed by filtration,dissolved in methylene chloride, washed with water, dried over anhydrousmagnesium sulfate and filtered through magnesium silicate to remove mostof the color. Evaporation of the solvent under reduced pressure gives203g. of pink solid, melting point l30-l 32 C. Recrystallization of a5.0 g. sample from acetone-hexane gives 4.0 g. of 5-amino-3-ethyl-l-phenyl-4-pyrazoleearbonitrile as colorless crystals,melting point 1321 33 C.

EXAMPLE 2 5-Amino-3-ethy1-l-phenyl-4- Preparation of'pyrazolecarboxamide EXAMPLE 3 Preparation of5-Amino-3-ethyl-1-(m-flu0ropheny1)-4- pyrazolecarbonitrile A mixture of24.4 g. of m-fluorophenylhydrazine hydrochloride, 22.5 g. of(l-ethoxypropylidene)- malononitrile and 12.3 g. of anhydrous sodiumacetate in 300 ml. of absolute ethanol is refluxed for 23 hours, cooledand filtered. The filtrate is evaporated under reduced pressure to givea brown gummy residue. Crystallization from benzene gives, afterfiltration and washing with benzene, 22.2 g. of light tan crystals,melting point 128-13 1 C. Recrystallization of a 5.00 g. sample from 50ml. of benzene using activated charcoal gives 3.24 .g. of fluorophenyl)-4-pyrazolecarbonitrile as colorless crystals, melting point 130-l32 C.

EXAMPLE 4 Preparation of 5-Amino-3-ethyl-1-(m-fluorophenyl)-4-,

5-amino-3-ethyl-l-(mby filtration, washed with water and air-dried togive 5.25 g. of product, melting point 1l4-l 16 C. The crystals aredissolved in dichloromethane and chromatographed over silica gel. Thecolumn is eluted with ether (200 ml. cuts) and cuts 3-9 are combined andthe solvent is removed by evaporation under reduced pressure. Theresidual crystalline solid (4.37 g.) is recrystallized fromacetone-hexane to give 2.79 g. of 5-amino-3-ethyl-l-(m-fluorophenyl)-4-pyrazolecarboxamide as colorless crystals,melting point 124.5-l26 C.

EXAMPLE 5 Preparation of S-Amino-l-(m-chlorophenyl)-3-ethyl-4-pyrazolecarbonitrile A mixture of 22.5 g. of (1-ethoxypropylidene)-malononitrile, 36.1 g. of m-ehlorophenylhydrazine sulfate and 24.6 g. ofsodium acetate in 300 ml. of absolute ethanol is heated under reflux for24 hours. The mixture is evaporated under reduced pressure and theresidue is dissolved in a mixture of water and benzene. The benzenelayer is separated, washed with water, dried over magnesium sulfate andevaporated under reduced pressure to give 13.5 g. ofa dark gum whichsolidifies. Two recrystallizations from acetone-hexane give 9.5 g. ofS-amino-l-(m-chlorophenyl)-3-ethyl-4- pyrazolecarbonitrile as colorlesscrystals, melting point 1 l3-1 15 C.

EXAMPLE 6 EXAMPLE 7 Preparation of 50 gm. Tablets For Per 10,000 TabletTablets 0.050 g. 5-Amino-3-ethyl- 500 g.

l-(mfluoro- 1 phenyl)-4-pyrazolecarboxamide 0.080 Lactose 800 0.010 CornStarch (For Mix) 0.008 Corn Starch 80 (For Paste) 0.148 g. 1480 g. 0 002g Magnesium Stearate 20 0 150 g 1500 g.

The active ingredient, lactose andvcorn starch (for mix) are blendedtogether. The corn starch (for paste) is suspended in 600 ml. of water.and heated with stirring, to form a paste. This paste is then used togranulate the mixed powders Additional water is used. if necessary. Thewet granules are passed through a No. 8 hand screen and dried at F. Thedry granules are then passed through a No. 16 screen. The mixture islubricated with 1% magnesium stearate and compressed into tablets in asuitable tableting machine.

EXAMPLE 8 Preparation of Oral Syrup The sorbitol solution is added to 40ml. of distilled water and the active ingredient is suspended therein.The saccharin, sodium bcnzoate, flavor and dye are added and dissolvedin the above solution. The volume is adjusted to 100 ml. with distilledwater. Each ml. of syrup contains mg. of drug.

Other ingredients may replace those listed in the above formulation. Forexample, a suspending agent such as bentonite magma, tragacanth,carboxymethylcellulose or methylcellulose may be used. Phosphates,citrates or tartrates may be added as buffers. Preservatives may includethe parabens, sorbic acid and the like and other flavors and dyes may beused in place of those listed above.

EXAMPLE 9 Preparation of Parenteral Solution In a solution of 700 ml. ofpropylene glycol and 200 ml. of water for injection is dissolved 20.0 g.of 5- amino-3-ethyl-l-phenyl-4-pyrazolecarboxamide with stirring. Afterdissolution is complete, hydrochloric acid is added to adjust the pH to5.5 and the volume is made up to 1,000 ml. with distilled water. Theformulation is filtered through a 0.22 micron sterilizing filter. filledinto 5.0 ml. ampoules. each containing 2.0 ml. (representing 40 mg. ofdrug). and scaled under nitrogen.

We claim:

1. A pyrazolecarboxamide of the formula:

C ll

CONH

NHZ

wherein R is hydrogen, chloro or fluoro, or non-toxic acid addition saltthereof.

2. The pyrazolecarboxamide in accordance with Claim 1,5-amino-3-ethyl-l-phenyl-4- pyrazolecarboxamide.

3. The pyrazolecarboxamide in accordance with claim I,5-amino-3-ethyl-l-(m-fluorophenyl)-4- pyrazolecarboxamide.

4. The pyrazolecarboxamide in accordance with claim 1,5-amino-3-ethyl-l-phenyl-4- pyrazolecarboxamide hydrochloride.

5. The pyrazolecarboxamide in accordance with claim 1,5-aminol-(m-chlorophenyl)-3-ethyl-4-

1. A PYRAZOLECARBOXAMIDE OF THE FORMULA:
 2. The pyrazolecarboxamide inaccordance with claim 1, 5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamide.3. The pyrazolecarboxamide in accordance with claim 1,5-amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide.
 4. Thepyrazolecarboxamide in accordance with claim 1,5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamide hydrochloride.
 5. Thepyrazolecarboxamide in accordance with claim 1,5-amino-1-(m-chlorophenyl)-3-ethyl-4-pyrazolecarboxamide.